Acetaminophen, also commonly known as paracetamol, is a widely used active pharmaceutical ingredient. Its world demand is around 100,000 metric tons including more than 50% demand in United States of America. Acetaminophen is being prepared by Celanese, Mallinckrodt, Monsanto, and Sterling processes.
In the Celanese process, as described in U.S. Pat. No. 4,954,652, cited herein as a reference, acetaminophen is prepared by Beckman rearrangement of 4-hydroxyacetophenone oxime in an alkyl alkanoate as a solvent in the presence of a catalyst. The other three processes involve N-acetylation of 4-aminophenol with acetic anhydride in an inert solvent such as water, water-isopropanol mixture, acetic acid, ethylacetate, benzene and other suitable hydrocarbons. 4-Aminophenol is also extensively used for other applications such as in hair dye formulations, as rubber additive and in photographic developing agents, and is, therefore, being produced by several manufacturers across the world.
Thus, most of the manufacturers of acetaminophen use 4-aminophenol as the most commonly available starting material. Over the past decade significant efforts have been made to make chemical manufacturing environmentally friendly through the green chemistry approach. Attempts also have been made to minimize or eliminate the use of solvents in the manufacture of acetaminophen. For example, a solvent-minimized synthesis from 4-nitrophenol has been described in U.S. Pat. No. 6,969,775 B2, but this process employs still some undesirable reagents, Triton X-405 (a polyoxyethylene ether) and potassium thioacetate, as the catalyst system, which may end up in the product.
These materials or their degradation products can present a hazard if present as impurities in the product or as pollutants in the environment. On account of very high consumption of acetaminophen a more clean and economical process is needed for its production. Until now, there exists no cleaner method for the synthesis of acetaminophen than that disclosed in the present invention.